Alcoholism is a major public health problem in the U.S., but research into interaction with the brain is far from conclusive. We propose to investigate the effects of ethanol in the hippocampus and some of its inputs, in particular, the locus coeruleus. These structures are involved in regulating mood, anxiety and memory and are involved in other types of addiction (opiates). Experiments will be conducted on tissue slices in vitro. Ethanol and other drugs will be introduced into the superfusing medium in known concentrations, or applied iontophoretically. Cells will be impaled with glass micro-electrodes for intra-cellular recording and stimulation, and also will be voltage clamped using a one-electrode voltage clamp amplifier. Synaptic potentials will be elicited by extra- cellular stimulation. The following major research questions will be posed; 1) What is the mechanism of the dual effect of ethanol on neuronal excitability? Our work to date indicates that ethanol may both increase and decrease excitability. We propose to test a hypothesis according to which both effects are due to increased phophatidyl inositol degradation induced by ethanol, the suppression of excitability being due to the attendant changes in inositol tri-phosphate and the increases in excitability being caused by activation of protein kinase C. 2) Does ethanol affect any other protein kinase C sensitive mechanisms? We propose to study the effects of ethanol on a number of protein kinase C related mechanisms in hippocampus, locus coeruleus and dorsal raphe. This research program proposes to build on our existing excitability data and to follow a recent biochemical lead, namely the increased hydrolysis by ethanol of phosphatidyl inositol, to search for novel effects of ethanol. In the process we hope to gain insight into the role the phosphatidyl inositol system plays in the intoxication and addiction to ethanol.